2. Academic Validation
  3. Identification of benzothiazoles as novel PCSK9 inhibitors

Identification of benzothiazoles as novel PCSK9 inhibitors

  • Bioorg Med Chem Lett. 2023 Nov 6:129542. doi: 10.1016/j.bmcl.2023.129542.
Zhixin Ma 1,  Hongtao Liu 2,  Shan Jiang 1,  Wenya Li 1,  Yue Li 3,  Yiting Liu 3,  Li Wang 4,  Wenyan Li 5
Affiliations

Affiliations

  • 1 Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024, China.
  • 2 Department of Pharmacy, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.
  • 3 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • 4 NHC Key Laboratory of Biotechnology of Antibiotics and CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China. Electronic address: wangli@imb.pumc.edu.cn.
  • 5 Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024, China. Electronic address: wyli8512@mail.hebtu.edu.cn.
PMID: 37939861 DOI: 10.1016/j.bmcl.2023.129542
Abstract

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a clinically validated target on the treatment of Cardiovascular Disease (CVD). PCSK9 can regulate the hepatocyte surface low density lipoprotein receptor (LDLR) level by binding to LDLR and leading to their degradation in the lysosome. The clinical use of two monoclonal Antibodies (alirocumab and evolocumab, approved in 2015) and one small interfering RNA (inclisiran, approved in 2020) which can inhibit PCSK9 function proved that they are very effective in lowering low density lipoprotein Cholesterol (LDL-C). However, the high treatment costs and parenteral administration of these drugs prohibited widespread use and reduced their long-term advantage. Comparatively, small molecule drugs have many incomparable advantages of macromolecules, such as lower treatment cost, more drug administration options, superior pharmacokinetic properties, less adverse immunogenic responses and better affordable production. In this paper, we identified a series of benzothiazoles small molecule PCSK9 inhibitors through extensive screening. The structure and activity relationship (SAR) was summarized to facilitate further optimization. Moreover, the primary mechanism of action of the most potent compound was also investigated.

Keywords

Atherosclerosis; Low density lipoprotein cholesterol; PCSK9 inhibitors; Small molecule drugs.

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